Abstract

Cancer is known to result from genetic mutations, both inherited and somatic. Yet, decades of investigation and the availability of extensive genomic data, have failed to reveal the specific mutations that directly result in tumorigenesis for most cancers. One possible reason is that tumorigenesis may result from one or more of multiple different combinations of mutations, while investigators generally search for a single set of mutations. A mathematical model of the probability of “hitting” one of many possible combinations of a small number of mutations was compared to the actual distribution of accumulated mutations at diagnosis as reported on the cancer genome atlas (TCGA). This “multi-combination multi-hit” model reproduces the distribution of accumulated mutations from the TCGA database with surprising accuracy (RMSD = 1.5%) for a model where one or more of 100 different possible combinations of three mutations result in tumorigenesis. We speculate that each of the three mutations affects one of the several genes in three distinct cell proliferation control pathways, such as senescence, apoptosis, autophagy and necrosis, and different combinations of mutations affecting three of these pathways may result in tumorigenesis. We have identified several such combinations for further investigation.